Abstract How do the cell fates, lineages, and molecular histories of individual cells control the development and physiological function of tissues? This problem is of central importance throughout biomedical science. However, progress has long been limited by two seemingly intractable, and inter-related, challenges: First, we still have no method to determine the tree of lineage relationships among cells in developing tissues within their native spatial context. Second, we have no way to determine the sequence of extracellular signals and intracellular molecular events experienced by each cell in the developing tissue as it differentiates. Time-lapse imaging has been the principal go-to method to image biological processes in living systems. However, a large number of systems in biology and medicine do not permit live cell imaging methods because they are inaccessible or optically opaque, such as mouse brains and embryos. Thus, there is a crucial need to develop powerful new methods that can achieve inference of lineage information and cellular event histories from static end-point measurements. Here we propose to develop a platform that enables cells to record lineage and dynamic gene expression histories in their own genomes, within complex developing tissues. This platform will combine two recently developed tools: first, genome editing tools that can ?record? lineage information or cellular events into the genome, and second, a single molecule microscopy based in situ technology called sequential multiplexed Fluorescence In situ Hybridization (seqFISH) that can read out the recorded information in single cells without dissecting them out from tissues. We call this method MEMOIR (Memory through Enhanced Mutagenesis with Optical In situ Readout). Akin to using sequence variation for phylogenetic tree analysis, this method will allow us to reconstruct the lineage tree for a population of cells as well as the signaling event history within those cells based on the hierarchy of mutations incorporated into the target region. We have performed the proof-of-principle experiments in mouse embryonic stem cells (mESCs) and will extend the work to mouse embryos. We envision that MEMOIR will allow us to map lineages and signaling events directly in complex tissues such as the brain and track cells in metastatic tumors.